The association of centromere amplification and response to trastuzumab in HER2+ metastatic breast cancer.
Authors: Charlotte Andrieu, Dalal Al-Sultan, Laura Ivers, Jose Javier Berenguer Pina, Darko Skrobo, Josephine Ballot, Alex J. Eustace, Cecily Quinn, Giuseppe Gullo, Naomi Walsh, John Crown
Journal: Journal of Clinical Oncology (2023)

1016 Background: Chromosomal instability and copy number aberration (CNA) burden can be associated with patients' survival in some cancers. Centromeres, chromosomal regions crucial for genomic stability, can be found altered by CNA in tumours but remain largely unexplored due to sequencing technologies. Using whole-genome sequencing (WGS) data from cases of long term, never relapsed HER2+ metastatic breast cancer (MBC) patients, also referred as exceptional responders (ExRs), we aim to better characterise the CNA profiles and underlying long-term survival of this “exceptional” cohort and investigate the centromeric and pericentromeric association with prognosis and treatment response. Methods: Two hundred and forty-three HER2+ MBC patients were enrolled in the HER2 Patients Project Database from St Vincent University Hospital, Dublin, Ireland. Eighty-five HER2+ MBC patients were identified as exceptional survivors (ExS) with an OS &gt; 60 months (range 60-248 months), of which 28 never-relapsed and responded exceptionally (ExR) to trastuzumab. Patients with an OS &lt; 60 months (N=158, range 0.2-59 months) were identified as non responders (NR). WGS was performed on 13 ExR tumours (primary or metastases) and matching control at a mean depth of 60X and 30X, respectively. Control-FREEC and CNVkit were used to characterise the CNA profiles and estimate the CNA burden. Samples from 10 NR patients were used for comparison with the ExR. Results: WGS analysis revealed that ExR samples are more impacted by gain rather than loss of copy overall, with a median fraction altered by gain of 0.24. No significant difference was observed between the ExR and NR in terms of CNA burden. However, a large fragment on chromosome 9 was amplified in 92% of ExR (12/13) which corresponded to the centromere (chr9q11) and a large heterochromatic block (chr9q12). A higher copy number status of this centromeric region was detected in the ExR, with a gain of at least 1 additional copy compared to the NR tumoral samples (P&lt;0.001). The dichotomisation into high versus low copy number of the centromeric region of chromosome 9 was also observed in centromeres of chromosome 17 (P=0.009) and chromosome 19 (P&lt;0.001). No case of polysomy was detected in our cohort and genes located near the centromeres, such as ERBB2 (amplified in both ExR and NR), were independent of the centromeres copy-number status. Conclusions: The identification of the genomic aberrations of these metastatic patients, treated with trastuzumab who never relapsed, increases our understanding of the mechanisms involved in MBC progression. Our results suggest that the centromere co-amplification of chr9q11-q12, chr17p11.1-q11.1 and chr19p11-q11 stratifies patients according to their OS. CNA status of the centromeric regions of chromosomes 9, 17 and 19 may therefore represent a novel prognostic predictor to trastuzumab response and new outcomes for patients.